Project Abstract There are currently 1.6 million individuals with inflammatory bowel disease (IBD) in the US, with an estimated 70,000 new cases occurring each year. While the pathogenesis of IBD is multifactorial, the immune system plays a significant role. IBD's associated direct and indirect costs are estimated to amount up to a $30 billion economic burden annually. The heterogeneity and complexity of disease pathogenesis has made IBD difficult to effectively treat and our current understanding of the inflammatory process associated with disease have led to suboptimal treatment options. To date, anti-TNF therapies have proved the most effective option among IBD treatments. However, anti-TNF therapy is only effective in approximately 50% of patients and a substantial part of the responding patient population, approximately 20% per year, becomes refractory to treatment after some time. Thus, there is a clear and urgent need to identify novel regulators of IBD in an attempt to identify additional targets for therapeutic intervention. Previous GWAS studies focused on IBD have led to the identification of over 200 hundred genes with genetic variants that significantly associate with disease susceptibility, making IBD one of the most extensively studied diseases by GWAS. However, whether these genetic variants lead to a difference in gene expression has not been quantified. By analyzing IBD patient colonic gene expression, and comparing it to known GWAS-associated genes, I identified GPR183, encoding a protein known as EBI2, as a potentially novel regulator of intestinal inflammation. While an intronic single nucleotide polymorphism within GPR183 has been significantly associated with IBD risk, there is no known role for the receptor in disease. Our analysis revealed that expression of both GPR183 and the enzymes necessary for production of its ligand, 7?25HC, are increased in the colon of IBD patients compared to healthy controls and in two mouse colitis models. Literature shows that GPR183 expression is associated with a variety of other autoimmune diseases, including type 1 diabetes, multiple sclerosis, and systemic lupus erythematosus. Additionally, our preliminary data demonstrate that inhibition of GPR183 by a specific antagonist inhibits pathogenesis of colitis in a mouse model of disease. Inhibition of colitis pathogenesis was associated with improved weight gain, lengthening of the colon, and less severe histological features, compared to PBS- treated controls. Thus, our data, and data I have mined from the literature, support a novel role for GPR183 in IBD development and progression. The proposed studies will aim to determine the mechanism of action whereby GPR183 affects intestinal inflammation, including the critical cell type(s) expressing GPR183, as well as the identity of the cell types producing its ligand. Successful completion of these aims will significantly impact our understanding of IBD pathogenesis, as well as our understanding of an immune mechanism that has been associated with other autoimmune diseases.